Sodium-Glucose Cotransporter 2 Inhibitors and Risk of Hyperkalemia in People With Type 2 Diabetes: A Meta-Analysis of Individual Participant Data From Randomized, Controlled Trials

Circulation. 2022 May 10;145(19):1460-1470. doi: 10.1161/CIRCULATIONAHA.121.057736. Epub 2022 Apr 8.


Background: Hyperkalemia increases risk of cardiac arrhythmias and death and limits the use of renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, which improve clinical outcomes in people with chronic kidney disease or systolic heart failure. Sodium-glucose cotransporter 2 (SGLT2) inhibitors reduce the risk of cardiorenal events in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease. However, their effect on hyperkalemia has not been systematically evaluated.

Methods: A meta-analysis was conducted using individual participant data from randomized, double-blind, placebo-controlled clinical outcome trials with SGLT2 inhibitors in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease in whom serum potassium levels were routinely measured. The primary outcome was time to serious hyperkalemia, defined as central laboratory-determined serum potassium ≥6.0 mmol/L, with other outcomes including investigator-reported hyperkalemia events and hypokalemia (serum potassium ≤3.5 mmol/L). Cox regression analyses were performed to estimate treatment effects from each trial with hazards ratios and corresponding 95% CIs pooled with random-effects models to obtain summary treatment effects, overall and across key subgroups.

Results: Results from 6 trials were included comprising 49 875 participants assessing 4 SGLT2 inhibitors. Of these, 1754 participants developed serious hyperkalemia, and an additional 1119 investigator-reported hyperkalemia events were recorded. SGLT2 inhibitors reduced the risk of serious hyperkalemia (hazard ratio, 0.84 [95% CI, 0.76-0.93]), an effect consistent across studies (Pheterogeneity=0.71). The incidence of investigator-reported hyperkalemia was also lower with SGLT2 inhibitors (hazard ratio, 0.80 [95% CI, 0.68-0.93]; Pheterogeneity=0.21). Reductions in serious hyperkalemia were observed across a range of subgroups, including baseline kidney function, history of heart failure, and use of renin-angiotensin-aldosterone system inhibitor, diuretic, and mineralocorticoid receptor antagonist. SGLT2 inhibitors did not increase the risk of hypokalemia (hazard ratio, 1.04 [95% CI, 0.94-1.15]; Pheterogeneity=0.42).

Conclusions: SGLT2 inhibitors reduce the risk of serious hyperkalemia in people with type 2 diabetes at high cardiovascular risk or with chronic kidney disease without increasing the risk of hypokalemia.

Keywords: chronic; diabetes mellitus; heart failure; hyperkalemia; potassium; renal insufficiency; sodium-glucose transporter 2 inhibitors; type 2.

Publication types

  • Meta-Analysis

MeSH terms

  • Antihypertensive Agents / therapeutic use
  • Diabetes Mellitus, Type 2* / complications
  • Diabetes Mellitus, Type 2* / drug therapy
  • Female
  • Glucose
  • Humans
  • Hyperkalemia* / chemically induced
  • Hyperkalemia* / epidemiology
  • Hypokalemia* / chemically induced
  • Hypokalemia* / epidemiology
  • Male
  • Mineralocorticoid Receptor Antagonists / adverse effects
  • Potassium
  • Randomized Controlled Trials as Topic
  • Renal Insufficiency, Chronic* / drug therapy
  • Renal Insufficiency, Chronic* / epidemiology
  • Sodium
  • Sodium-Glucose Transporter 2 Inhibitors* / adverse effects


  • Antihypertensive Agents
  • Mineralocorticoid Receptor Antagonists
  • Sodium-Glucose Transporter 2 Inhibitors
  • Sodium
  • Glucose
  • Potassium